This grant is focused on determining those changes which occur earliest in Duchenne dystrophy, the most common dystrophy. Other dystrophies, myopathies and neuromuscular diseases are studied to assess the significance and specificity of the changes detected. Specific aims include: 1) study of energy metabolism in the diseases listed previously with particular emphasis on (a) C14-fatty acid activation and oxidation by muscle homogenates and (b) oxidative phosphorylation of fatty acyl-carnitines by mitochondria isolated from the same biopsies of patients with dystrophies, myopathies and neurogenic muscular atrophies; 2) studies of the abnormality of fragmented sarcoplasmic reticulum (FSR) from patients with clinically early Duchenne dystrophy. The "leakiness" and rate of passive efflux of calcium from the FSR will be assessed together with kinetic parameters using the assay for calcium concentrating ability of FSR. The origin of the electron dense bodies will be sought and correlated with the defect of calcium concentration. Other studies focus on the chemical composition, enzyme activity and morphology of sarcolemma isolated from normal and diseased human and animal muscle; 3) studies of the defect in ATPase activity and superprecipitation of natural actomyosin in Duchenne dystrophy. Myosin isolated from normal and diseased muscle will be combined with actin from diseased and normal muscle respectively in order to further characterize the abnormal superprecipitation; 4) continued characterization of the three types of fibers (fast-twitch red, fast-twitch white, and slow-twitch intermediate) in guinea pig muscle with specific reference to correlation of biochemical, histochemical and contractile properties; 5) studies of exercise-induced changes in skeletal muscle with focus on determining the time course of appearance and disappearance (after cessation of exercise) of such changes and their relation to increase in strength and endurance of the same muscle of trained versus control (sedentary) animals. BIBLIOGRAPHIC REFERENCES: Peter, J.B. The Etiology of Duchenne Muscular Dystrophy: The Biochemical Evidence. In Proceedings of the 3rd International Congress on Muscle Diseases. W.G. Bradley, Ed. Excerpta Medica. p.148 (1975).